Coccidioidomycosis: New Aspects of Epidemiology and Therapy Author(s): Hans E. Einstein and Royce H. Johnson Source: Clinical Infectious Diseases, Vol. 16, No. 3 (Mar., 1993), pp. 349-354 Published by: Oxford University Press Stable URL: http://www.jstor.org/stable/4456953 . Accessed: 05/11/2014 21:42
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349
CLINICALARTICLE STATE-OF-THE-ART
Coccidioidomycosis:New Aspects of Epidemiologyand Therapy
Hans E. Einstein and Royce H. Johnson
From the Departmentsof Medicine, BakersfieldMemorial Hospital and Kern Medical Center,Bakersfield,and the USC and UCLA Schools of Medicine, Los Angeles, California
And I saw anothersign in heaven. .. sevenangels having the seven last plagues . .. And the seventhangelpouredout his vial into the air . -Revelations
Mycology C. immitisis a normalinhabitantof the sandy and somewhat saline soil of the.lowerSonoranDesert life zone, where it grows in the mycelial form. The warm, dry environment that producesarthroconidia breakfromthe parentmycelium and waft in the wind. When these are inhaled by an appropriatehost, primary pulmonaryinfection occurs. Within the convertto spherules,which acinus,arthroconidia pulmonary then reproduce endosporulation. is Thus, Coccidioides deby finedas a genus of thermaldimorphic The efficiencyof fungi. endosporulationas a reproductiveprocess accounts for the rapidgrowthof the organisms. Immunology The main containment mechanismfor control of the infectious processis cell-mediatedimmunity.Individualswith substantialsuppressionof T cells develop severepulmonary and, frequently,disseminateddisease. Down-regulationof cell-mediatedimmunityalso occurs duringthe latter stages of pregnancyand in the early postpartumperiod. During these stages women are particularly susceptibleto developthe disseminatedforms of the disease, especiallyif they ing are of a susceptibleracialgroup(table 1). The immunologic response to coccidioidal infections results in productionof both IgM and IgG antibodies. However, neither of these is in antibodprotective; fact,the amountof complement-fixing ies producedis inverselyproportional the host'sprospects to of resolvingthe infection.
History is Coccidioidomycosis the oldest of the majormycoses,on the basis of reportsin the literature.The first case was reported in 1892 and occurredin an Argentinesoldier.Thus, last yearrepresented centennialof its discovery.The case the was erroneouslyreportedas that of mycosis fungoides.Soon there followed reportsfromSan Franciscodescribingthe disorderas a protozoaninfection. It was not until the work of Ophuls in the early partof this century that the diseasewas properlyclassifiedas a mycosis and the causativeorganism identifiedas Coccidioides immitis.In the late 1930s, Gifford recognized that the organism that she recovered from the sputum of many patients sufferingfrom a well-known, selflimited pulmonaryinfection known as San Joaquin Valley fever was the same as the agent describedby Ophuls in his report of frequently fatal coccidioidal granuloma. C. E. Smith and his colleagues, under the auspices of the Armed Forces Epidemiological Board, defined the clinical syndromeof primary disseminatedcoccidioidaldiseasedurand the Second World War. They outlined the areaof endeing micity, recognizedthat there were distinct racialdifferences in the occurrenceof dissemination,and developeda seriesof highly sensitive and specific immunologic diagnostic tests. Theirworkestablisheda scientificbasisof researchthat, with the isolationof the antibioticamphotericin led to the theraB, peutic era. The addition of the imidazole group of drugsto the armamentarium followed, and the introduction in the 1980s of the orally active azole derivativesopened yet another era of therapyfor coccidioidomycosis.
Epidemiology Coccidioidomycosisis found only in the WesternHemisphere.Foci ofendemicity exist in specificareasof Argentina and CentralAmerica,in the southwesternUnited States(includingand west of El Paso,TX), and in the contiguousparts of northwestern Mexico. Areasof highestendemicityare the southernSan JoaquinValley of California and southernArizona, hence the popular term for the primarypulmonary manifestationof coccidioidomycosis,valleyfever. The geographicdistributionis that of the lower SonoranDesert life zone, markedby relativelylow annual rainfall,soils that are sandy and high in salt, and periodicdust storms. The disease strikes individualsof any age, but cases in-
Received 24 November 1992. Reprintsor correspondence:Dr. Hans E. Einstein, Medical StaffOffice, BakersfieldMemorial Hospital, 430 34th Street, Bakersfield,California 93301. ClinicalInfectiousDiseases 1993;16:349-56 ? 1993 by The University Chicago. rights of All reserved. $02.00 1058-4838/93/1603-0001
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for of Table 1. Riskfactors dissemination coccidioidomycosis.
reportablein California,such reportingis farfromcomplete. In Kern County, California,a unique resourcefor performAge group:Infantsand the elderly ing serologictestingexists at the Public Health Department. Sex: Male Approximately90%of all coccidioidal serologies in Kern native American,Hispanic,Oriental Race: Filipino, African-American, County are performedat this laboratory.This allows the orderof greatestriskto least risk) (in numberof cases to be trackedin a fairlyconstant and comSkin test: Negative SerumCF titer:> 1:64 plete fashion. The numberof positive serologiesconfirmed Pregnancy:Second half of pregnancyand postpartum at the health departmentlaboratory a typicalyear is 250; in Malignancy,chemotherapy,steroiduse, Immunosuppression: from September1991 throughJanuary 1992, however,that seropositivityfor human immunodeficiencyvirus numberincreasedto 967 (figure 1). In the summer of 1992, an increase in the incidence of coccidioidomycosis was again detected. Figures from the and very old patients often have the Kern County Public Health Departmentshowed a dramatic volving very young risein the numberofseropositivepatientsaftera shorthiatus worst clinical outcomes. Most cases occur in late childhood in the early springof 1992, when the numberof cases was throughearly middle age. The incidence of pulmonarydisas does that of exease shows a slight male preponderance, relatively normal. The peak incidence occurredduring the firstweek of November 1992, when 270 cases were reported disease. The latter occurs more frequentlyin trapulmonary females who acquire the infection during the latter half of (table 2). The numberof cases occurringin that 1 week approximatesthat found in a typical year. The overall incipregnancyor in the early postpartumperiod. The incidence of primarypulmonarydisease shows no racialpredilection. dence of serology-proven coccidioidomycosisrepresentsan increaseover usual patterns.Sixty percent of cocHowever, disseminationclearly occurs more commonly in eightfold certain racial groups; among persons of Filipino, African- cidioidal infections are asymptomatic;of the other 40%, American, Hispanic, native American, and oriental extrac- fewerthan one-thirdareclinicallyevaluated.Thus, the numberof infectionsconfirmedserologically only - 8%-10% tion (in that order),the incidence of disseminateddiseaseis is of the total numberof infections. increased(table 1). A dust storm in Californiain 1977 provided a naturalmeans of confirmingthis increasedrisk;durThere is no obvious reason for this marked increase in this storm, large amounts of arthroconidia-containing cases. However, after a 5-year droughtin this region, relaing dust from the southernSan JoaquinValley were transported tively significantamounts of rain fell in March 1991 and in to the northernand coastal areasof the state. The incidence Februaryand March 1992. This may have broughton the of disseminated coccidioidomycosis in the non-Caucasian germinationof arthroconidia (which requiresmoisture)from population was disproportionateto its overall representa- myceliaaccumulatedover 5 years.In 1991, unusuallysevere tion. dust probablycontributedto the more efficientdispersionof Epidemics of coccidioidomycosis have been reported these arthroconidia.Similar, although less severe, drought under several differentcircumstances.Some of these might conditions preceded the dust storm-related epidemic that be better describedas small outbreaksrelated to construc- occurredin early 1978. tion, archaeological digs, or exploration for oil in areas where, apparently, substantial numbers of arthroconidia were in the soil. The firstof these outbreaksthat was recogDiagnosis nized occurred because of a substantial change in demographics. During World War II large numbers of military Diagnosis of coccidioidomycosisis dependenton the prewere stationed in the southernSan Joaquin Valsentationof an indicativeclinical syndrome.Knowledgeof a personnel ley. Coccidioidomycosisbecame the majorhealth problem. patient's history of exposure throughtravel or residencein the area of endemicity is helpful; cases occur at substantial However, this was an epidemic only in the sense that large numbersof cases occurredbecause of the introductionof a distances from the foci of endemicity by virtue of fomite previously unexposed population into dusty environments transmission.Diagnosis can be confirmedby cultureof the in the area of endemicity. The firstknown true epidemic of media. There is some diffifunguson appropriate laboratory C. coccidioidomycosisoccurredfollowing the 1977 dust storm culty in distinguishing immitisfroma varietyofnonpathomentioned above, which caused the incidence of coccidioigenic fungi. Animal inoculationsmay need to be performed and domycosisin 1978 to quadruplein California to increase for obtaininga positive identification;newer techniquesin20-fold in the San Joaquin Valley. volving DNA probeidentificationof a suspectedisolate may obviatethis procedure.Biopsymaterialthat showsa granuloCurrently, a major epidemic of coccidioidomycosis is under way in California.Early in the fall of 1991, several matous histopathologicresponse to infection and contains in characteristicspherules with evidence of endosporulation practitioners the areasof endemicitynoted an increasein the numberof cases of primarydisease. While the disease is may also confirmthe diagnosis.Examinationof tissue, fluid,
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CID 1993;16(March)
and Coccidioidomycosis: Epidemiology Therapy
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in Kern Coccidioidomycosis County
Comparison
800 700 0 600 500 400 300 200 104 100
0
of
Normal
and
Epidemic
Years
741
Normal Year
1991
~ 1992
547 415
(2 weeks)
256 184 86 50 21 30 91
Jan
Feb
Mar Apr May Jun
Jul
Aug Sep
Oct
Nov Dec
Figure 1. Illustrationof the increasein the numberof cases of coccidioidomycosisin Kern County, California.
and pus with special fungal stains (e.g., Grocott-Gomori methenamine-silver nitrate) is helpful. Cytological stains provide an excellent way of showing fungal elements in fluid, pus, and fine-needle biopsy specimens. fromthe availableskin-testagentsprepared Commercially mycelial or spherularform of the fungusare available.Both are adequatefor detecting evidence of a currentor previous infection with the fungus. The utility of the skin test in the areaof endemicityis limited since >50%of the adult population typically have a positive reaction; those with early or severe forms of the disease frequentlyhave a negative skin test. The presence of substantialor prolonged coccidioidal infection despite a persistentlynegative skin test is a poor prognosticfactor. The serologicaltests available for detection of coccidioidomycosis are very sensitive, and many of them are quite specific. They can be divided into two categories:those that detect IgM antibodiesand those that detect IgG antibodies. The latex agglutinationtest, which has been commercially availablefora numberof years,detects IgM. It is fairlysensitive but produces a large number of false-positiveresults; therefore,it is not recommended.The classic tube precipitin test is both sensitiveand reasonablyspecificfor IgM. This is also true of the immunodiffusion test, which can detect both
IgG and IgM antibodies. The newest and perhapsbest test forIgMantibodyis the enzymeimmunoassay (MeridianLabit is sensitiveand specific.Immunodiffuoratory,Cincinnati); sion tests and the enzyme immunoassayalso can be used for detection of IgG antibodies. However, there have been instances in which the enzyme immunoassaywas negative for antibodIgG and IgM, yet high levels of complement-fixing ies were detected by other methods. The immunodiffusion test for IgG appearsto have a sensitivityequal to that of the CF test, althoughthey clearlydo not detectthe sameantibodies and theirresultsdo not necessarilyhave the sameimplication regarding prognosis. The most useful test availableremainsthe CF test for IgG antibodies. This test, which is less sensitive than the IgM tests describedabove and some immunodiffusion IgG tests, has the advantageof giving prognosticas well as diagnostic information.A titerof complement-fixing antibodiesof> 1:4 reflectsthe presenceof recent or currentcoccidioidalinfection. The presence of higher titers increasesthe likelihood that the disease is currentlyactive, and it is inverselycorrelated with a salutaryoutcome. While no titer of complement-fixingantibodies predictswith precision the presence of disseminateddisease,highertitersreflectan increasedrisk for metapulmonary spreadand are cause for concern.
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Clinical Manifestations Coccidioidomycosispresentsas primary,progressivepulmonary,and disseminateddisease. Its most frequentform is asymptomaticpulmonaryinfection, the presenceof which is indicatedby a positive skin test. Individualswith this condifor tion are infectedasymptomatically life in much the same way that individualswith a positive purifiedprotein derivatuberculosis. tive skin test are infected with Mycobacterium are of patientswith coccidioidomycosis asympSixty percent tomatic. Others have a respiratoryillness characterizedby fever, cough, and headache,often with associatedsymptoms of malaise,myalgia,and fatigue.These infectionsare usually mild and of short durationand are passedoff by the patient or care-giveras an influenza-likeillness. In approximately one-fourthof the symptomaticcases, the manifestationsare more severe and include pleuritic chest as pain.These casesareoften diagnosedinaccurately commupneumonia;most are ultimatelyappropriately nity-acquired diagnosed,usually by means of serologyor culture.The majority resolve uneventfully;only a minorityprogressto complicated pulmonarydisease or disseminateddisease. Skin manifestations primary of coccidioidalillness are prenodosum or erythemamultiforme.It dominantly erythema has been reportedthat these rashessuggesta benign prognosis. Indeed, most cases that involve erythema nodosum or erythemamultiformehave a good outcome, but no more or less so than cases that involve no skin manifestations.Skin lesions in association with other substantialrisk factorsdo not appearto negate the effect of the latter,and dissemination results.Arthritisis seen in associationwith primary cocThe ankle is the most commonly and most cidioidomycosis. severely involved joint. The arthritisis usually reasonably symmetricaland can involve severaljoints. This self-limited syndromehas historicallybeen known as desertrheumatism and representsan immune complex reaction, not disseminated coccidioidaldisease.
accompaniedby persistenceof a cavity or coccidioidalpulmonary abscess (usually described in terms of its radioas graphicappearance thin-walled)or of a pulmonarynodule The latter pathologicallyrepresentsan in(coccidioidoma). spissatedcavity. The persistenceof either of these lesions is evidence of an immunologic and anatomic focalization of the disease;disseminationis rarelyseen in this setting.They a represent local destructiveprocess,the resultof pneumonic caseation. The coccidioidoma presents a problem from a diagnosticpoint of view only when it is discoveredincidently in the bronchopulmonary segment in a patientwith no hisof primarycoccidioidal pneumonitis. Serologicaland tory skin tests are frequently negative in this setting. Thus, a since calcificationocbiopsy is often required,particularly curs in only 12% these lesions. The etiology of the cavity of can often be diagnosedfrom study of sputum, bronchopulmonary lavage fluid, or fine-needle biopsy specimens. The naturalhistoryof the cavities allows one to predictthat approximatelyone-thirdwill close within the first2 yearsafter their discovery. In two-thirds of cases, persistent cavities cause bleeding that at times is severe and thus may necessitate excision. Rupture occurs occasionally, particularlyin subpleurallocations, and leads to empyemaformation.Secondary infections of cavities also occur. Chronic persistent disease, resemblingchronic pulmonaryhistofibrocavitary or tuberculosis, is occasionally seen in persons plasmosis with preexistingbronchopulmonary disease.This tends to be slowly progressive,responds poorly to medical or surgical therapy,is frequentlybilateral,and rarelydisseminates.
Disseminated Disease Disseminated disease occurs in - 1%of individuals infected by C. immitis;it is definedas coccidioidaldiseasethat spreadsbeyond the pulmonaryparenchymaor hilar node. has Coccidioidomycosis been found in virtuallyevery organ of the body except the gastrointestinal tract.The most common site of diseasespreadis the skin, wheregranulomasdevelop; they have a variety of morphologicalappearances, from clusters of pustules to classic granulomas.Additional cutaneous involvement occurs as cold subcutaneous abscesses. The second most frequenttypes of disseminatedinfection are synovitis and osteomyelitis. A wide variety of bones are involved, including the vertebra,skull, ribs, and long bones. In terms of affectedjoints, the disease shows some predilectionfor the knee, ankle, wrist,and elbow. Additional loci include the eye, larynx,epididymis,and peritoneum. The most severe manifestationof disseminatedcoccidioidomycosis and the entity responsible for the majority of deaths due to this disease is meningitis.It may occur within 2-3 weeks of the onset of pulmonarydisease or may follow
and Pulmonary Complications Sequelae Coccidioidalprimary pneumoniais characterized a pulby infiltrate that is frequently subpleural and often monary abuts fissures.Pleuraleffusionsoverlie a subpleuralinfiltrate in 12% the cases. The effusion usually clearsas the pneuof monitis does. Hilaradenopathyis frequent;paratracheal and mediastinaladenopathy, however, are not part of superior the primarycomplex and may signal dissemination. Diffuse, so-called miliaryinfiltrationsare seen duringthe secondaryhematogenouspulmonaryphase in earlydissemination. The clearingof the pulmonaryinfiltrateis usuallyin concertwith the subsidenceof the adenopathy;shouldeither persist,progressiveprimarydisease results. In -5% of cases, clearing of the pulmonaryinfiltrateis
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CID 1993;16(March)
and Epidemiology Therapy Coccidioidomycosis:
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Table 2. Systemic therapyfor nonmeningealcoccidioidomycosis.
Dose Drug AmphotericinB Ketoconazole Fluconazole Itraconazole Indication Severe or potentially severe disease Mild-to-moderate stable disease Mild-to-moderate stable disease Not defined Route iv po po po Initial 1-5 mg 400 mg 400 mg 400 mg Usual 50 mg 400 mg (rarelyhigher) 400-800 mg 600 mg (?) Total (or duration) 1-3 g (3 mo to severaly) (3 mo to severaly) Not defined
an asymptomaticpulmonaryinfection. Meningitisrarelyappears long after the pulmonarydisease;the longest interval of which we are aware is 12 years. Meningitismay be relaor tively indolent and slowly progress may runits full course, from onset of symptoms to death, within a matterof a few weeks. Meningitisis complicatedby local neurologicaldeficits causedby directcranialnerveinvolvement(due to vasculitis) that producesa strokelikesyndromeor transverse myelitis. Hydrocephalus is also a frequent and severe complication. Patientsinfectedwith the human immunodeficiencyvirus involvement.While dissemiusuallypresentwith widespread nated coccidioidomycosisis not as severe or as frequentas histoplasmosisor cryptococcosisin this patient population, several hundredsuch cases have been reported.The overall responseof these patientsto therapyhas been disappointing.
Treatment Beforethe introductionofamphotericinB in 1957, a large numberof agentswere triedfor the treatmentof coccidioidomycosis; none of these had any lasting effect. Intravenous of amphotericinB remainsthe "gold standard" therapy.For most patients with primarydisease and some patients with limited disseminateddisease, the infection resolves without treatment. Because of its significant toxicity, therapywith amphotericinB is reservedfor those with severedisease(i.e., patientswho have extensive and rapidlyprogressive primary disease, who are at risk for disseminationof disease, or who have documented disseminated disease). A dose of 1-3 g (occasionallymore) of amphotericinB is given in 50-mg increments as daily or thrice weekly infusions administered over 1-2 hours.The intensityand durationof therapyis determined by the severity of the disease and its response to therapy.Most cases of pulmonarydiseaseand diseaseof limited disseminationrequirea total dose of 1-2.5 g. The introduction of the azoles-miconazole, ketoconazole, fluconazole, and, most recently, itraconazole-has added a new dimension to therapyfor coccidioidomycosis.
Ketoconazole has been most extensively studied with patients who have pulmonaryinfection and nonmeningealdisseminateddisease. Similarstudies of fluconazole have been reported.Only limited data are available pertainingto itraconazole. No studies of treatmentof primarydisease with azoles have been performed,and no comparativestudies have been undertaken.Despite this lack of data, ketoconazole and, more recently,fluconazolehave been used to treat moderate primary pulmonary infections (table 2). These drugshavealso been usedin an attemptto preventdissemination, to treat limited disseminateddisease,and as follow-up therapy for patients whose conditions did not respond or only partially responded to therapy with amphotericinB. The overall responseto treatmentwith azoles appearssomewhat less than that to treatmentwith amphotericinB; relapses occur in about one-third of patients treated with azoles. The investigationalliposomal amphotericinand amphotericincholesterylsulfatepreparations appearto offeran advantage over amphotericinB in that with their decreased toxicity (particularly nephrotoxicity), administration of largerdoses is possible. amMeningitisremainsmost difficultto treat.Intrathecal B has been the standardof therapyfor 35 years. photericin Intravenousamphotericinalone is not efficaciousfor treatment of meningealcoccidioidomycosis,a circumstancethat this distinguishes diseasefromcryptococcosis. Amphotericin B must be given intrathecallyby direct lumbaror cisternal or injection or via a ventricular cisternalOmmayareservoir. The longest experiencehas been with protracted intracisternal administration.Treatment needs to be continued for many months and should be guided by clinical and spinal fluid findings (e.g., cell count, protein and glucose levels, and titer of complement-fixing antibodies).The averagetolerateddose is 0.5 mg. Recently, data have accumulatedon the use of fluconazole in the treatmentof CNS coccidioidomycosis.This drug is investigationalfor this indication, but preliminarydata show it has efficacyat doses of >400 mg daily. The response is slowerand less surethan that with amphotericin but the B, drug'stoxicity is negligible.Fluconazolemay be more effec-
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tive in higher doses; 800-mg, 1,200-mg, and even higher doses have been administeredexperimentally,but no data exist on outcome. Limiteddataexist on the utilityofitraconazole forboth systemicand CNS coccidioidomycosis; defino nite recommendationcan be made at this juncture. AmphotericinB given by local injectionsor irrigation, particularly in a joint space or surgicalsite, is useful either as primarytherapy or as an adjunct to systemic and surgical therapy.Interarticular injectionsofamphotericinB prepared in sterile water of appropriate volume can be administered. The dose is escalatedfrom 5 mg to 15 mg, dependingon the of patient'stolerance,and administration the drugis continued for 2-4 weeks(one to threetimesa week). Subsequently, the frequencyof injections is graduallydecreased;the total period of treatmentis -6 months. Surgicalremoval of involucraand sequestrais important in the treatmentof osteomyelitis.Adjunctivein-and-outirrigation tubes may be placed at surgeryand used for continuous irrigationwith 50-100 mg of amphotericinin 1 L of sterilewaterover 24 hours.This treatmentcan be continued for 7-14 days if the tube remainsunobstructed.
Acknowledgments The authors express appreciation to R. Talbot, Ph.D., and G. Welch, M.P.H., of the Kern County, California, Health Department, and also to C. Middaugh and J. Weaver for secretarial assistance.
Suggested Readings 1. Drutz DJ, CatanzaroA. Coccidioidomycosis.Parts I and II. Am Rev RespirDis 1978; 117:559-85, 727-71. 2. Galgiani JN. Fluconazole, a new antifungal agent. Ann Intern Med 1990; 113:3:177-9. 3. Galgiani JN, Ampel NM. Coccidioidomycosisin human immunodeficiency virus-infectedpatients.J Infect Dis 1990;162:1165-9. 4. Graybill JR, Stevens DA, Galgiani JN, Dismukes WE, Cloud GA, NIAID MycosesStudyGroup. Itraconazoletreatmentof coccidioidomycosis. Am J Med 1990;89:282-90. 5. TerrellCL, HughesCE. Antifungalagents used for deep-seatedmycotic infections. Mayo Clin Proc 1992;67:69-91. 6. TuckerRM, GalgianiJN, Denning DW, et al. Treatmentofcoccidioidal meningitiswith fluconazole. Rev Infect Dis 1990;12(suppl 3):S3809.
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